NM_138619.4:c.1880T>C

Variant names:

• chr17-75238984-A-G
• NM_138619.4:c.1880T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138619.4(GGA3):​c.1880T>C​(p.Val627Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GGA3 NM_138619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

GGA3 (HGNC:17079): (golgi associated, gamma adaptin ear containing, ARF binding protein 3) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. Multiple alternatively spliced transcript variants have been identified in this gene. [provided by RefSeq, Feb 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138619.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA3	NM_138619.4	MANE Select	c.1880T>C	p.Val627Ala	missense	Exon 15 of 17	NP_619525.1	Q9NZ52-1
	GGA3	NM_014001.5		c.1781T>C	p.Val594Ala	missense	Exon 14 of 16	NP_054720.1	Q9NZ52-2
	GGA3	NM_001172703.3		c.1664T>C	p.Val555Ala	missense	Exon 15 of 17	NP_001166174.1	Q9NZ52-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGA3	ENST00000537686.6	TSL:1 MANE Select	c.1880T>C	p.Val627Ala	missense	Exon 15 of 17	ENSP00000438085.3	Q9NZ52-1
	GGA3	ENST00000538886.5	TSL:1	c.1781T>C	p.Val594Ala	missense	Exon 14 of 16	ENSP00000446421.2	Q9NZ52-2
	GGA3	ENST00000621870.4	TSL:1	n.*1839T>C		non_coding_transcript_exon	Exon 16 of 18	ENSP00000479464.1	G3V1K5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.3
PrimateAI	Uncertain	0.62	T
REVEL	Uncertain	0.30
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.58		Loss of catalytic residue at V627 (P = 0.1218)
MVP		0.73
ClinPred		0.96	D
GERP RS		5.2
PromoterAI		-0.0060	Neutral
Varity_R		0.70
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr17-73235065;